What Is the Krebs Cycle and What Is Its Function?

Todya, we're going to explain in a simple way one of the bases of aerobic metabolism: The Krebs cycle. This route is essential for the genesis of energy.

Written and verified by el nutricionista Saúl Sánchez.

Last update: 01 July, 2023

The Krebs cycle is one of the most important metabolic pathways for obtaining energy. It’s included within aerobic metabolism and is a very efficient mechanism that turns out to be a key element in cellular respiration. It’s also known as the citric acid or tricarboxylic acid cycle.

We’re going to explain what exactly the Krebs cycle consists of, how it develops, and what its importance within the body is. Keep in mind that it is an essential process for life and whose activation above normal can determine the state of body composition.

How does the Krebs cycle take place?

The main substrate of the Krebs cycle is acetyl-CoA, a molecule that results from the process of aerobic glycolysis. It’s a mechanism that takes place in the matrix of the mitochondria and has an oxidative nature. In addition to the acetyl-CoA molecule, a unit of NADH and carbon dioxide are obtained, key elements in the process of obtaining energy.

The Krebs cycle is made up of a set of 8 reactions modulated by different enzymes. In total, four oxidations are carried out. Acetyl-CoA undergoes a series of transformations that are catalyzed over time. Some of them are reversible, but others aren’t.

At first, the acetyl-CoA molecule combines with oxaloacetate to form citrate. This releases a couple of carbon dioxide molecules. From here, a compound known as GTP is generated that aims to reduce certain compounds, which ends with the restoration of the initial oxaloacetate. The cycle could be repeated again.

When there’s a complete cycle of the entire system, two CO2 molecules are released, and three NADH, one FADH2, and one ATP or GTP are produced. These last two elements are those used for energy production. They can be obtained from the Krebs cycle itself, although there are other metabolic reactions that generate them through different substrates.

It must be taken into account that the Krebs cycle occurs 2 times for each glucose molecule contributed to the cellular respiration process. From this, two pyruvates are obtained, which later become two acetyl-CoA.

Oxidative phosphorylation

When the Krebs cycle is concluded, metabolic pathways are set in motion that end up generating a large number of ATP molecules. Among them, the electron transport chain stands out, in which the NADH and FADH2 generated at the end of the previous cycle are introduced. During this process, electrons are transported from the mitochondria to the intermembrane space, through the action of proteins.

Each time an electron transfer is experienced, energy that can be used is released. However, most of it is produced in the last step of this chain, in which a good part of the electrons returns to the mitochondrial matrix through an enzyme called ATP synthase.

It must be taken into account that 80% of the ATP generated by the degradation of the glucose molecule is produced at this point, thanks to the electron transport chain. It’s an oxygen-dependent mechanism, as, at the end of the chain itself, water is formed. In the absence of the molecule, the process is paralyzed.

What is the Krebs cycle for?

The main function of the Krebs cycle is the genesis of energy at the mitochondrial level. Thanks to this metabolic route, ATP molecules can be obtained. They’re not only obtained through glucose metabolism, but their genesis from amino acids or fatty acids is also possible.

When glucose levels in the body are low, or glycogen stores are depleted, a pathway called the beta-oxidation of fatty acids is activated. From here, there’s a mobilization of the lipids accumulated in the body, as well as the circulating fats, for the production of energy.

However, these elements don’t enter the Krebs cycle or cellular respiration as such, but rather undergo a series of conversion processes to the acyl-CoA complex. This substrate enters the interior of the mitochondria where it undergoes a series of conversion processes until a unit of acetyl-CoA is obtained. This can enter the Krebs cycle in a normal way for the production of ATP.

In any case, it must be taken into account that fatty acids are capable of generating a much higher energy yield than sugars or proteins. While these last two nutrients provide approximately 4 calories per gram, lipids are capable of offering up to 9 calories per gram.

When is the Krebs cycle activated?

The Krebs cycle is constantly activated, otherwise, life couldn’t exist. It’s one of the main mechanisms for obtaining energy. Together with the aerobic respiration processes, it’s part of a complex of reactions that are quite efficient in terms of energy performance, much more than all those of the anaerobic type that are promoted in the face of intense efforts.

In any case, the Krebs cycle gains even more prominence when performing long-lasting resistance exercises of medium or moderate intensity. In this case, aerobic metabolism is the main process for obtaining energy. The objective, in this case, is to save muscle glycogen, as otherwise, fatigue would appear prematurely.

It must be borne in mind that the efficiency of the cycle itself is a trainable capacity, especially with regard to the beta-oxidation process of fatty acids. When resistance exercises are carried out, the body tries to avoid the excessive consumption of glucose, thus increasing the rate of conversion of fatty acids and amino acids into acetyl-CoA.

To maximize the efficiency of this process and improve glycogen savings, certain external ergogenic aids can be used, such as caffeine. This has been shown to be capable of increasing sports performance and delaying the onset of fatigue, according to a study published in the journal Sports Medicine. However, optimal dosages should be used.

Although energy production through the Krebs cycle predominates during endurance efforts, the other metabolic pathways aren’t “turned off”. Those of an anaerobic nature continue to function, although they lose part of their weight and their prominence. Similarly, in a situation of maximum effort, the Krebs cycle continues to work, although its energy contribution to the total is lower.

How to lose weight by stimulating the function of the Krebs cycle

Most weight-loss diets seek to increase the function of the Krebs cycle, stimulating the previous beta-oxidation of fatty acids to generate a mobilization of adipose tissue. For this, several different strategies can be taken. One of the most classic has to do with calorie restriction. When there’s a lack of circulating glucose, the stored reserves will be used.

There are also certain mechanisms that stimulate a process called autophagy. This could have the characteristic of reducing the risk of developing cancer, according to research published in the journal Clinics. From autophagy, inefficient proteins and cells are eliminated, being replaced by others that perform their functions well.

It’s a mechanism that goes hand in hand with increasing the efficiency of lipid oxidation. Therefore, an increase in insulin sensitivity and a greater capacity of the body to mobilize fats to produce energy is achieved, saving glycogen and stimulating weight loss from adipose tissue.

The best way to activate this whole process is by starting the intermittent fasting protocol, by means of which calorie intake is restricted for a period of time not less than 16 hours. While the restriction lasts, the Krebs cycle and the rest of the aerobic metabolism routes will be the protagonists in terms of obtaining energy.

Just the same, any habit that manages to increase metabolic flexibility will be positive for activating the Krebs cycle and fat oxidation, thus improving body composition. For this, the practice of physical exercise can be decisive, especially strength work. It generates a muscle hypertrophy process that has been shown to promote metabolic efficiency and weight loss.

The ketogenic diet and the activation of the Krebs cycle

One of the diets committed to activating the Krebs cycle and increasing the efficiency in the oxidation of fatty acids is ketogenic. This is based on the restriction of carbohydrate intake, which manages to generate an increase in the feeling of satiety and progressive weight loss. This is stated by research published in the journal Nutrition & Diabetes.

In this context, the importance of anaerobic metabolism is reduced. Most of the energy produced is generated during cellular respiration. In addition, the lipid oxidation processes are stimulated. It’s necessary to replenish glycogen stores through its transformation and ensure that there are substrates to initiate the Krebs cycle.

Regardless, the ketogenic diet creates a very characteristic metabolic state known as ketosis. In this context, ketone bodies are the preferred substrates of the brain. Increased metabolic flexibility is experienced from increased insulin sensitivity.

However, the ketogenic diet causes certain short-term transient side effects, which are insurmountable for some. These drawbacks can condition adherence to treatment, leading many of its practitioners to abandon the regimen during its first days.

The ketogenic diet, Krebs cycle, and sports

This feeding method is proposed in certain sports contexts seeking an increase in the efficiency of the use of lipids for the genesis of energy. It’s a common strategy within the framework of endurance sports. In the medium term, it can translate into an increase in performance and a delay in the onset of fatigue in competition.

When the ketogenic diet is applied during high-intensity physical exercise, a process known as keto-adaptation occurs. From it, the ketone bodies generated during metabolism are capable of meeting 75% of the energy needs of the brain.

There’s an increase in the enzymes responsible for oxidizing fatty acids. In addition, these immediate principles begin to be used by other cells in the body, such as nerve cells. Therefore, their energy requirements are satisfied. Even the heart muscle could make use of these elements for their functions.

Regardless, professional supervision is recommended. If it’s not well regulated, intestinal problems and deficiencies of essential nutrients that affect well-being can be experienced. Fiber supplementation is usually necessary in these cases to avoid alterations in the microbiota. Pre and probiotics are also beneficial in these contexts.

Diseases related to the Krebs cycle

There are some developed or acquired diseases that can condition the proper functioning of the Krebs cycle. Many key points around this issue are still unknown, but certain inefficiencies have been identified in terms of cycle development that can lead to serious health problems.

Some of the problems could come from excessive nutrient deprivation. For example, in the case of a thiamine deficiency, problems are experienced in the oxidation of pyruvate, which could limit the production of acetyl-CoA to start the Krebs cycle. The deficiency of this vitamin is especially dangerous for the brain.

In fact, there are certain diseases that can develop from a situation of this style, beriberi being the best known. It’s a common disease in people with excessive dietary restrictions or dependent alcohol users. In both situations, excessive concentrations of pyruvate in the blood will be detected.

Other conditions can generate similar situations. For example, when mercury or arsenic poisoning occurs, very similar symptoms are experienced. It’s normal in these cases for there to be problems in the central nervous system generated from a defect in the metabolism of pyruvate.

In both cases, the brain is deprived of a sustained source of energy, as the Krebs cycle is one of the main routes that allow the maintenance of its functions. The moment in which the main organ of the central nervous system isn’t supplied optimally, important inefficiencies begin to occur in its functions.

Other mitochondrial diseases

In addition to the aforementioned diseases, there may be other mitochondrial diseases that hinder the metabolic processes carried out in these cellular organelles. The most frequent have to do with alterations in the genetic material of these elements. This can condition the synthesis of endogenous determinant proteins for the mitochondria to fulfill its functions.

In most cases, it’s necessary to resort to pharmacological measures to solve these problems. The application of a strong antioxidant that intervenes in the electron transport chain within the mitochondria, such as coenzyme Q10, usually works well. High doses are used to try to correct the defects in the organelle and restore homeostasis.

According to a study published in the International Journal of Molecular Science, coenzyme Q10 is decisive for achieving a good function at the mitochondrial level. If a deficiency is experienced, alterations will be generated that can condition the efficiency of the metabolism, causing chronic and complex diseases in the medium term.

There are also vitamins that are decisive when it comes to ensuring mitochondrial health. Riboflavin would be one of them. Also, vitamin K and vitamin C play important roles, as they have a marked antioxidant character. Even substances such as L-carnitine are decisive in allowing the entry of substrates into the cell.

In fact, it was long believed that L-carnitine supplementation could stimulate weight loss from fat oxidation. However, current evidence suggests that positive results aren’t experienced, except in the case of obese people. For this reason, it makes no sense to introduce the element into the nutritional guideline of a person who wants to improve their body composition.

The Krebs cycle: An essential part of aerobic metabolism

The Krebs cycle is a cornerstone of aerobic metabolism. On the one hand, use the results of the decomposition of pyruvate for the genesis of energy. On the other, it creates the necessary substrates to activate the electron transport chain, one of the most efficient processes in terms of ATP synthesis.

One of the main characteristics of this metabolic mechanism, apart from its cyclical nature, has to do with the possibility of using different energy substrates. The process is capable of starting with a glucose molecule. Also, fatty acids and amino acids can start the cycle if they undergo a series of previous transformations.

Be that as it may, the Krebs cycle is a determining process in the synthesis of energy. If it doesn’t work, life becomes impossible. In fact, all diseases that alter mitochondrial homeostasis are considered complex and serious. They have disastrous consequences for health in the medium term and their treatment through pharmacology is necessary.